The goal of this proposal is to test the hypothesis that the reduction of key autophagy gene expression and autophagy function as a result of DNA damage during the aging process plays a key role in mediating the onset of Huntington's disease (HD). Mouse, Drosophila and C. elegans models of HD suggest that the cytotoxicity of expanded polyglutamine is highly dependent upon protein context and protein expression levels of mutant Htt. Autophagy plays an important role in regulating the intracellular accumulation of mutant Htt with expanded polyQ. The expression of beclin 1, a key gene involved in autophagy, decreased in an age-dependent fashion in human brains. Since beclin 1 gene is haploid insufficient in regulating autophagosome function, age-dependent decrease of beclin 1 expression may lead to a reduction of autophagic activity during aging. The hypothesis is that reduction of autophagy function in aging results in both increased oxidative stress induced DNA damage and reduced long-lived protein turnover which promotes the accumulation of mutant Htt. Increased accumulation of mutant Htt and oxidative stress may play an important role in promoting the onset of HD. This hypothesis will be tested in the following specific aims. Specific Aim 1 is to test,the hypothesis that the reduction of beclin 1 expression in aging human brains contributes to the onset of HD by generating beclin 1+/-; HdhQ111 mice and examining if 50% reduction of beclin 1 expression led to an increased accumulation of mutant Htt as well as to determine the consequence of autophagy deficiency on neuronal survival and functions. Specific Aim 2 is to examine the mechanism which led to the age-dependent reduction of beclin 1 expression by testing if the promoter of beclin 1 is preferentially damaged in aging human brains and particularly susceptible to oxidative damage in cellular models. The contribution of reduced expression of transcriptional factors regulating beclin 1 expression will also be considered. Specific Aim 3 is to test the hypothesis that the reduction of autophagy function exacerbates the DNA damage during aging by increasing the accumulation of damaged mitochondria which further promotes the levels of intracellular ROS by examining aging beclin 1+/- mice and autophagy deficient cells for evidence of increased damaged mitochondria. Specific Aim 4 is to investigate the functional role of autophagy to oxidative DNA damage using CK-p25 mice as a model and to examine the roles of of DNA damage and autophagy deficiency to the accumulation of mutant Htt in HdhQ111; CKp25 mice. The ability of SIRT1 activating molecules (STACs) to restore the autophagy function in CK-p25 mice and to delay the onset of motor dysfunction in HD models will be determined. Understanding the mechanism by which DNA damage negatively regulates autophagy during aging would allow us to develop strategies to maintain normal autophagy function during aging process which may delay or prevent the onset of HD and other aging related neurodegenerative diseases.